Modulation of androgen signaling to innate immune killing of prostate cancer

Abstract

Described are improved therapies for the treatment of cancer including prostate cancer.

1 . A method of treating prostate cancer in a patient in need thereof comprising administering a therapeutically effective amount of an androgen receptor inhibitor and an agent that activates natural killer (NK) cells to the patient. 
     
     
         2 . The method of  claim 1 , wherein the androgen receptor inhibitor is selected from darolutamide or enzalutamide. 
     
     
         3 . The method of  claim 1 , wherein the androgen receptor inhibitor is selected from flutamide, nilutamide, bicalutamide, apalutamide, proxalutamide, BMS-641988 or TRC-253. 
     
     
         4 . The method of  claim 1 , wherein the agent that activates NK cells is selected from a natural killer cell receptor NKG2A inhibitor, or a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-inducing compound. 
     
     
         5 . The method of  claim 4 , wherein the NKG2A inhibitor is monalizumab. 
     
     
         6 . The method of  claim 4 , wherein the TRAIL-inducing compound is a compound of formula 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 1 , comprising administration of one or more additional therapies selected from surgery, radiation therapy, poly (ADP-ribose) polymerase (PARP) inhibitors, checkpoint inhibitors, or chemotherapy. 
     
     
         8 . The method of  claim 1 , wherein administering an androgen receptor inhibitor increases expression of non-classical human leukocyte antigen E (HLA-E) on NK cells. 
     
     
         9 . The method of  claim 1 , wherein administering an androgen receptor inhibitor increases expression of programmed cell death ligand (PD-L1) on NK cells. 
     
     
         10 . The method of  claim 1 , wherein administering an androgen receptor inhibitor increases secretion of interferon gamma (IFN-γ) from NK cells. 
     
     
         11 . The method of  claim 1 , wherein administering an androgen receptor inhibitor increases secretion of granzyme B from NK cells. 
     
     
         12 . The method of  claim 1 , wherein the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC). 
     
     
         13 . The method of  claim 1 , wherein the patient has been previously treated with androgen deprivation therapy (ADT). 
     
     
         14 . A method for activating NK cells comprising contacting NK cells with an androgen receptor inhibitor. 
     
     
         15 . The method of  claim 14 , wherein the androgen receptor inhibitor is selected from darolutamide or enzalutamide. 
     
     
         16 . The method of  claim 14 , wherein the androgen receptor inhibitor is selected from flutamide, nilutamide, bicalutamide, apalutamide, proxalutamide, BMS-641988 or TRC-253. 
     
     
         17 . A method for treating a cancer associated with androgen receptor signaling in a patient in need thereof comprising administering a therapeutically effective amount of an androgen receptor inhibitor and an agent that activates natural killer (NK) cells to the patient. 
     
     
         18 . The method of  claim 17 , wherein the cancer is prostate cancer, breast cancer or melanoma. 
     
     
         19 . A method for resensitizing treatment resistant prostate cancer cells, the method comprising modulating the expression of HLA-E in the prostate cancer cells. 
     
     
         20 . The method of  claim 19 , wherein the expression of HLA-E in prostate cancer cells is modulated by contacting the cancer cells with an androgen receptor inhibitor and monalizumab.